The family of fibroblast growth factors (FGFs) includes 23 polymorphic growth factors with associated structures. Fibroblast growth factor-2 (FGF-2), which is one of the members of the FGF family, was extracted from bovine pituitary by American scientist Gospodsrowicz D in 1974, and is widely present in the cells derived from mesoderm and neural ectoderm as well as from various tumor cells. It activates a FGF receptor on the membrane of a target cell, mainly in an autocrine and/or paracrine manner, to induce a series of intracellular signaling, and involves in various physiological and pathological processes such as embryonic development, angiogenesis, nerve regeneration, tumor growth, etc.
FGF-2 has an isoelectric point, PI>9. 0, and is also referred to as a basic fibroblast growth factor (bFGF). The gene of FGF-2 is located in a human chromosome at 4q26, with a full length of 38 kb, comprising 3 exons and 2 introns. The mRNA of FGF-2 has multiple translation initiation sites, which can produce FGF-2 subtypes with various molecular weights, including subtype with a low molecular weight of 18 kd and subtypes with high molecular weights of 22, 22.5, 24 and 34 kd, but the FGF-2 with a low molecular weight of 18 kd which comprises 155 amino acid residues dominates. Low molecular weight subtypes are expressed in cytoplasm and membrane of a cell, while high molecular weight subtypes mainly directly enter into nuclei to function.
Acute lung injury (ALI) is an injury of alveolar epithelial cells and capillary endothelial cells due to a variety of direct and indirect injury factors, which can cause diffuse interstitial and alveolar edema in lung, resulting in acute hypoxic respiratory dysfunction. ALI is pathophysiologically characterized by reduced lung volume, decreased lung compliance, and imbalanced ratio of ventilation/blood flow; clinically characterized by progressive hypoxemia and respiratory distress; and characterized in lung imaging by inhomogeneous exudative lesions, called acute respiratory distress syndrome as it develops into a severe stage (oxygenation index<200). Common ALI-inducing factors are divided into direct and indirect lung injury factors, wherein direct lung injury factors include, for example, severe lung infection induced by viruses, bacteria and fungi, aspiration of gastric contents, lung contusion, oxygen poisoning, etc.; indirect lung injury factors include, for example, sepsis, shock, massive blood transfusion, cardiopulmonary bypass (CPB), disseminated intravascular coagulation (DIC), etc.
Lung injury is clinically characterized by: (1) acute onset, occurring within 12-48 hours after a direct or indirect pulmonary trauma; (2) difficulties to correct hypoxemia after conventional oxygen inhalation; (3) non-specificity of lung signs, hearable moistrales or decreased breath sounds in both lungs at acute phase; (4) early lesions, mainly interstitial, with no significant change in chest x-ray film (C-XF), but occurrence of lung consolidation after progression of disease, characterized by generally increased density, decreased transparency, increased and thickened lung markings, and visiable, discrete, patch-like, density-increased shadows in both lung fields; (5) shadows of diffuse pulmonary infiltrates, with no evidence of cardiac dysfunction.
Lung injury is clinically diagnosed through standards of: (1) acute onset; (2) an oxygenation index (Pa02/Fi02)≤200 mm Hg ((1 mm Hg=0.133 kPa, regardless of positive end expiratory pressure (PEEP) level; (3) patch-like shadows in both lungs shown in anteroposterior C-XF; (4) pulmonary artery wedge pressure (PAWP)≤18 mm Hg, or no clinical evidence of increased pressure in left atrium. For example, it may be diagnosed as ALI when showing Pa02/Fi02≤300 mm Hg and meeting other standards described above.
Lung injuries induced by respiratory viruses, bacteria, or fungi are the most common acute respiratory infections in clinic. Among these, influenza is a common and frequent disease affecting extremely widely on people, and there is now a grim situation of cross-species infection by influenza virus. Infection with influenza A virus H1N1 leads to clinical symptoms which are relatively mild in most patients, characterized in typical influenza-like symptoms, and can be recovered naturally. The most common symptoms include cough, fever, sore throat, headache, and other discomforts. Severe pneumonia patients have visible multiple lesion infiltration in C-XF, which can rapidly develop into ARDS, kidney or multi-organ failure. The incidence of influenza A combined with ARDS may be 100 folds of normal influenza. Lung damages are primarily derived from uncontrolled systemic immune response, and like ARDS that is secondary to viral pneumonia, include diffuse alveolar damage, bronchiolar and perivascular lymphocytic infiltration, hyperplastic airway changes, and bronchiolitis obliterans.
Both of clinical and pathological examinations indicate that serious patients may have lesions mainly in the respiratory system. It can be seen from a pathological examination that serious patients may have consolidation in lung, often accompanied with pathological changes such as bleeding, effusion, abscessus, etc. Serous effusion or fibrinous effusion found in alveolar space, accompanied with varied degrees of transparent film formation, which is indicative of diffuse lung injuries. It is currently considered that the basic lesions of pulmonary tissue injuries induced by influenza A virus H1N1 is similar to those of lung in serious cases resulted from other types of influenza, SARS, RSV, adenoviruses, parainfluenza, recently emerged SARS-like viruses, Human avian influenza H7N9, etc, i.e., varied degrees of diffuse pulmonary tissue injuries.
Lipopolysaccharides (LPSs), which are a group of water-soluble and glycosylated lipoplexes, are important ingredients in outer membrane of a gram-negative bacterium, and formed of three parts of lipid A, core polysaccharide and antigen O. LPS have a molecular weight of more than 10000 Daltons, with a complicated structure. Lipid A is a glycolipid contributive to endotoxin activity, covalently linked to a heteropolysaccharide chain. Human is extremely susceptible to bacterial endotoxin, and even a very small amount (1-5 ng/1000 g body weight) of endotoxin can induce an increased body temperature, a fever reaction which often lasts for about 4 hours and then gradually subsides. In the case of a natural infection, because of continuous growth and proliferation of gram-negative bacteria, accompanied with one after another death and release of endotoxin, the fever reaction will last until pathogens are completely eliminated in the body.
Fever reaction is induced by endotoxin because the endotoxin acts on macrophages and the like in bodies to produce cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor-α, etc., which in turns act on the thermotaxic center of hypothalamus in the host, resulting in increased body temperature and fever. Endotoxemia has clinical symptoms mainly depending on host's resistance to endotoxin, and the symptoms and signs thereof can include: fever, a changed number of leukocytes, a bleeding trend, heart failure, renal function insufficiency, liver damage, neurological syndromes, and shock, etc. Endotoxin can cause release of histamine, serotonin, prostaglandin, kinin, and the like, leading to expansion of microcirculation, reduced volume of venous return blood, decreased blood pressure, inadequate tissue perfusion, hypoxia, acidosis, etc.
Fungi can also affect lung tissues and result in lung injuries which may be mainly characterized by fungal inflammation or related diseases in lung and bronchi, and possibly those in pleura or even mediastinum. Pathogenic fungi belong to primary pathogens, which often induce a primary exogenous infection in an individual with normal immune function. Conditioned pathogenic fungi, alternatively called opportunistic fungi, have low pathogenicity, mostly inducing a deep fungal infection in a susceptible host.
Zymosans are macromolecular polysaccharide complexes extracted from yeast cell walls, formed of proteins and carbohydrates. Zymosans can be used to induce inflammations in lab, and the induced reactions thereby mainly include expression of inflammatory cytokines, upregulation of arachidonic acid, phosphorylation of partial proteins and formation of lipositol. Moreover, zymosans are capable of upregulating the expression of cyclin D2, which indicates that zymosans also play a role in the process of activation and proliferation of macrophages.
The infection with LPS in combination with zymosan may be used to simulate ALI induced by septicemia in vivo. Septicemia refers to an acute systemic infection induced by a pathogen or a conditioned pathogen which invades into blood circulation, and then grows and proliferates in blood, thereby producing toxins. Septicemia is one of risk factors of ALI, and one of the characteristics of septicemia-induced lung injury (SLI) is aggregation and activation of polymorphonuclear neutrophils (PMN) in pulmonary microvassels, giving rise to a series of inflammatory reactions and vascular injuries. In this process, bacterial infection, particularly gram-negative bacterial infection may be a key factor for initial inflammatory reaction. Gram-negative bacteria and LPS, after entering into a circulation, produce a LPS-binding protein (LBP), which will bind to a part of phospholipid A of LPS. The LPS-LBP complex bind to CD14 receptors on mononuclear cells, macrophages, and main neutrophils in plasma, to facilitate the translation of coding genes of specific inflammatory factors (such as TNF-a, IL-1, IL-6). The cytokines are secreted into circulation, which is an important biochemical characteristic in a series of inflammatory reactions responsible for septicemia and lung injuries. These cytokines such as IL-1, IL-6, IL-8, IL-10, IL-12, etc. will induce a series of cascade reactions, and participate the process of lung injury. Therefore, use of the infection with LPS in combination with zymosan may allow for a simulation of septicemia-induced lung injury.
To this end, there is already a great and urgent need for developing a new drug for the treatment and/or prevention of lung injuries in the life sciences.